Project Summary The goal of the proposed work is to characterize the transgenerational genomic impact of genocide exposure and post-traumatic stress disorder (PTSD) in women survivors of the Rwandan genocide and their offspring. PTSD is a common and debilitating mental disorder that has a profound public health impact. Between April and June 1994, almost one million people died in the Rwandan genocide against ethnic Tutsi. Twenty years later the long-term impact is illustrated by the prevalence of PTSD in Rwandan adults at 26.1 % and there is strong evidence pointing towards the transgenerational transmission of PTSD. PTSD has a known etiologic component: exposure to an extreme traumatic stressor involving life threat, which induces a biological cascade that includes epigenetic modification of loci whose activity contributes to psychopathological development. In addition, our study in Rwanda showed that transmission of PTSD to the offspring of genocide-exposed mothers was associated with transmission of biological alterations of the hypothalamic-pituitary-adrenal (HPA) axis and epigenetic modifications of the glucocorticoid receptor (NR3C1) gene, a key player in the glucocorticoid receptor regulatory network (GRRN). Building upon these recent findings, the proposed work seeks to characterize the transgenerational epigenetic effects of PTSD and trauma exposure due to the Rwandan genocide. We will employ genome-scale technologies and focus initial analyses on regulation of GRRN and related HPA axis genes, which have been associated with PTSD in recent genome-wide work. Specifically, we will test 100 DNA samples from our existing biobank, previously established in support of our pilot study. We will extend the existing biobank by collecting new specimens from women who were pregnant during the Rwandan genocide and their resulting children, as well their younger siblings, and a demographically matched, non-genocide exposed control group. We will perform additional analyses on a subsample of these specimens both in Rwanda and through the H3Africa network to test additional hypotheses. Our proposal is directly aimed at a key mission of RFA-RM-16-015, to support human genomics research that will not only generate important findings relevant to human health, but also serve as a vehicle to improve the research capacity of African laboratories and scientists at the institutions where the research is carried out. It also directly addresses NIMH strategic objectives 1.2: Identify the genomic and non-genomic factors associated with mental illnesses and 2.1: Characterize the developmental trajectories of brain maturation and dimensions of behavior to understand the roots of mental illnesses across diverse populations. The unique collaboration between the University of Rwanda, the University of Illinois and members of the H3Africa Network will also strengthen the capacity of scientific research through scientific training in Rwanda.